Toxoplasma gondii requires its plant-like heme biosynthesis pathway for infection
| Autor: | L. Brock Thornton, Daniel C. Whitehead, Kerrick C. Rees, Melanie Key, Amy Bergmann, Zhicheng Dou, Iqbal Hamza, Carly Dameron, Katherine Floyd |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Protozoan Proteins
Artificial Gene Amplification and Extension Biochemistry Polymerase Chain Reaction Toxoplasma Gondii chemistry.chemical_compound Medicine and Health Sciences Biology (General) Post-Translational Modification Heme Phylogeny Plant Proteins Protozoans 0303 health sciences biology 030302 biochemistry & molecular biology Eukaryota Plants Protoporphyrinogen oxidase Toxoplasma Toxoplasmosis Intracellular Research Article QH301-705.5 Immunology Biosynthesis Research and Analysis Methods Microbiology Parasite Replication Cofactor 03 medical and health sciences Virology parasitic diseases Organelle Parasitic Diseases Genetics Humans Protoporphyrinogen Oxidase Molecular Biology Techniques Molecular Biology 030304 developmental biology Apicoplast Host Cells Organisms Biology and Life Sciences Proteins Toxoplasma gondii RC581-607 biology.organism_classification Parasitic Protozoans chemistry biology.protein Parasitology Immunologic diseases. Allergy Viral Transmission and Infection |
| Zdroj: | PLoS Pathogens PLoS Pathogens, Vol 16, Iss 5, p e1008499 (2020) |
| ISSN: | 1553-7374 |
| Popis: | Heme, an iron-containing organic ring, is essential for virtually all living organisms by serving as a prosthetic group in proteins that function in diverse cellular activities ranging from diatomic gas transport and sensing, to mitochondrial respiration, to detoxification. Cellular heme levels in microbial pathogens can be a composite of endogenous de novo synthesis or exogenous uptake of heme or heme synthesis intermediates. Intracellular pathogenic microbes switch routes for heme supply when heme availability fluctuates in their replicative environment throughout infection. Here, we show that Toxoplasma gondii, an obligate intracellular human pathogen, encodes a functional heme biosynthesis pathway. A chloroplast-derived organelle, termed apicoplast, is involved in heme production. Genetic and chemical manipulation revealed that de novo heme production is essential for T. gondii intracellular growth and pathogenesis. Surprisingly, the herbicide oxadiazon significantly impaired Toxoplasma growth, consistent with phylogenetic analyses that show T. gondii protoporphyrinogen oxidase is more closely related to plants than mammals. This inhibition can be enhanced by 15- to 25-fold with two oxadiazon derivatives, lending therapeutic proof that Toxoplasma heme biosynthesis is a druggable target. As T. gondii has been used to model other apicomplexan parasites, our study underscores the utility of targeting heme biosynthesis in other pathogenic apicomplexans, such as Plasmodium spp., Cystoisospora, Eimeria, Neospora, and Sarcocystis. Author summary Toxoplasma gondii infects essentially all warm-blooded animals due to its broad species and tissue tropism. Almost one-third of the human population carry Toxoplasma infection, which can cause severe morbidity and mortality in immunocompromised individuals. The current antibiotics against Toxoplasma trigger strong side effects in some groups of patients and have limited efficacy on congenital toxoplasmosis. Thus, an urgent need for novel therapeutics exist. Here, we show that Toxoplasma gondii actively produces heme, a key nutrient for many subcellular activities, via its plant-like heme biosynthesis pathway for intracellular growth and acute virulence. We found that several herbicidal heme biosynthesis inhibitors and their derivatives show inhibitory effects against intracellular Toxoplasma growth. Our findings provide evidence that disrupting heme production in Toxoplasma could be an effective therapeutic strategy to control infection. |
| Databáze: | OpenAIRE |
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